Salts of indole derivatives and a process for preparing the same

ABSTRACT

Alkali metal salts or organic amine molecular compounds of such 1-acyl-3-indolylaliphatic acid derivatives as 1-(pchlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid, 1cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid or 1nicotinoyl-2-methyl-5-methoxy-3-indolylacetic acid are prepared by dissolving about 1 mole of said 1-acyl-3-indolylaliphatic acid derivative in acetone or methanol, reacting in the presence of a small amount of water the resultant solution with about 0.5 mole of alkali metal carbonate, or about 1 mole of alkali metal bicarbonate or with about 1 mole of an organic amine and distilling off acetone or methanol and water from the reaction mixture to yield the alkali metal salt or organic amine molecular compound. Alkaline earth metal or aluminum salt or said 1-acyl-3indolylaliphatic acid derivative is prepared by reacting a soluble salt of alkaline earth metal or aluminum with an aqueous solution containing said alkali metal salt of 1-acyl-3indolylaliphatic acid derivative. These alkali metal salts or organic amine molecular compounds are enable to make solid injections for anti-inflammatory drugs.

United States Patent Sato et a].

[ 51 June 13,1972

[72] Inventors: Nobuyasu Sato, ltami-shi; Toshlo Nakamura; HiroshiTakenaka, both of lbaragi-shi,

all of Japan [73] Assignee: Sumltomo Chemical Company, Ltd.,

Osaka, Japan [22] Filed: Aprll9, 1968 21 Appl. No.: 719,939

[30] Foreign Application Priority Data April 11, 1967 Japan ..42/23337[52] US. Cl. ..260/326.13 A, 424/266, 424/274,

[56] References Cited UNITED STATES PATENTS 3,161,654 12/1964 ShenH260/326.l4 X 3,190,889 6/1965 Shen .260/32614 X 3,242,185 3/1966 Shen..260/326.l3 X

O' ll l IiR PUl9l lCATlONS Blatt Qrganic S y ntheses," Collective Volume2, frontispage MN 5-METHOXY' 3 -INDOLYLACT/C ACID j and pages 376 to377, John Wiley and Sons, NY 1943 l-lickinbottom, Reaction of OrganicCompounds 2nd Ed., frontispage and pages 224 to 225, NY 1948, Longmans,Green andCo.

Primary Examiner-John D. Randolph Attorney-Stevens, Davis, Miller &Mosher [5 7] ABSTRACT Alkali metal salts or organic amine molecularcompounds of such l-acyl-3-indolylaliphatic acid derivatives asl-(pchlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid, 1-cinnamoyl-2-methyl-5-methoxy-3-indoly1acetic acid or I-nicotinoyl-2-methyl-5-methoxy-B-indolyiacetic acid are prepared bydissolving about 1 mole of said l-acyl-3-indolylaliphatic acidderivative in acetone or methanol, reacting in the presence of a smallamount of water the resultant solution with about 0.5 mole of alkalimetal carbonate, or about 1 mole of alkali metal bicarbonate or withabout 1 mole of an organic amine and distilling off acetone or methanoland water from the reaction mixture to yield the alkali metal salt ororganic amine molecular compound.

Alkaline earth metal or aluminum salt or said l-acyl-3-in dolylaliphaticacid derivative is prepared by reacting a soluble salt of alkaline earthmetal or aluminum with an aqueous solution containing said alkali metalsalt of l acyl-3-indolylaliphatic acid derivative. These alkali metalsalts or organic amine molecular compounds are enable to make solidiniections for anti-inflammatory drugs.

4 Claims. 17 Drawing Fiaures ZUYL)2-METHYL- P'A'TENTEDJM 1 a 19723,669,987

sum as or 11 ALUMINUM SALT OF l V (P- CHLOQOBENZOYL 2 -METHYL 5 ME THOXY 3 INDOLYLACETIC ACID PKTENTEDJummn 3.669.987

sum 12 or 11 FIG. /2A

SOD! UM SALT OF N NICOTINOYL -2 -METHYL- 5 -METHOX Y 3 INDOLYLACE TICACID I I I l I 25 a 9 /0 n I? 13 14 /5 I7 19 2/ z; lw I 1 I I I I I I II I I I 13a A260 mob so o 60 0 400 FIG. I28

PATENTEDJUH 13 m2 3. 669. 9 8 7 sum 17 or 17 ALUMINIUM SALT OF NCINNAWYL 2 METHYL 5 ME THOX Y 3 INDOLYLACETIC ACID J 25;! 3 4 5 6 7 a /wI T I I FIG. /7B

The present invention relates to salts of indole derivatives and aprocess for preparing the same. More particularly it relates to alkalimetal, alkaline earth metal or aluminum salts or organic amine molecularcompounds of l-acyl-B-indolylaliphatic acid derivatives.

l-acyl-3-indolylaliphatic acid derivatives in the present invention haveremarkable anti-inflammatory and anti-pyretic activities. However, thel-acyl-3-indolylaliphatic acid derivatives are extremely difficult todissolve in water, and among these l-acyl-3-indolylaliphatic acidderivatives, for example, l-( p-chlorobenzoyl)-2-methyl-S-methoxy-B-indolylacetic acid is a weak acid of pKa 4 andits solubility in water is 20-30 g/mL, and therefore it is difficult toprepare the injection thereof.

Further, in the case of administration of the tablet thereof, the effectthereof is irregularly exhibited due to diversed rate of absorption,which results in a side effects such as gastrointestinal upset or thelike. Therefore, it has been generally used in the form of capsules.

As the process for producing a sodium salt and potassium salt of somel-acyl-3-indolylaliphatic acids, U.S. Pat. No. 3,294,811 disclosed theprocess, which comprises dissolving a-trifluoromethyl-a-[l-(S-chlorothiazol-Z-carbonyl)-2 methyl-5-methoxy-3-indolyl]acetic acidin methanol at 0 C., adding thereto sodium methylate dissolved inmethanol, condensing the resultant mixture at 20 C., under reducedpressure, and adding thereto ether to recover the corresponding salttherefrom. Another U.S. Patent, No. 3,271,4l6 disclosed a process forproducing sodium salt, which comprises reacting in a nitrogen stream a-(l-benzyl-Z-methyl-S-amino- 3-indolyl)propionic acid with sodiummethylate, condensing the reaction product and adding thereto ether torecover the corresponding sodium salt therefrom.

However, in practicing these known processes, the compounds are prone tocoloring, etc. due to hydrolysis of l-acyl group and oxidativedeterioration. Therefore, it is indispensable to conduct temperaturecontrol and to carry out the reaction in a nitrogen stream, whichresults in an extreme complication of operations. That is, none of theseprocesses has been found satisfactory from an industrial point of views.

One object of the present invention is to provide a process forproducing salts or molecular compounds of l acyl-3-indolylaliphatic acidderivatives.

Another object of the present invention is to provide novel molecularcompounds of l-acyl-3-indolylaliphatic acid derivatives.

Other object of the present invention will be apparent from thefollowing description.

In order to accomplish these objects, the present invention provides aprocess for preparing alkali metal salts or molecular compounds ofl-acyl-3-indolylaliphatic acid derivatives represented by the formula,

wherein R is hydrogen or halogen atom, an alkyl having up to threecarbon atoms or an alkoxy having up to three carbon atoms, R is an alkylhaving up to three carbon atoms, R is hydrogen atom or an alkyl havingup to three carbon atoms, R is an alkali metal, or an organic amineresidue, and A is a phenyl substituted by halogen atom at an optionalposition, styryl or pyridyl, which comprises adding about I mole of thel-acyl-3-indolylaliphatic acid derivative represented by the formula,

wherein R, R', R and A have the same meanings as defined in the formula(I), to an organic solvent, preferably acetone or methanol, and reactingin the presence of a small amount of water the resultant mixture withabout 0.5 mole of carbonate or about 1 mole of bicarbonate of an alkalimetal, or about 1 mole of organic amine, for example ethanolamine,triethanolamine, diethylaminoethanol, ethylenediamine, histidine,arginine, lysine, omithine, citrullin, glucosamine, aminopyrine,chlorpheniramine, ergotamine, urotropin, thiamine or pyridoxamine toyield the alkali metal salt or the organic amine molecular compound ofthe formula I.

Further the present invention provides a process for producing alkalineearth metal or aluminum salts of l-acyl-3- indolylaliphatic acidderivative represented by the formula,

wherein R, R R and A have the same meanings as defined above and R is analkaline earth metal or aluminum, which comprises reacting a solublesalt of an alkaline earth metal or of aluminum with the said alkalimetal salt represented by the formula (I) in the presence of water toyield the alkaline earth metal or aluminum salt of the formula (Ill).

Furthermore the present invention provides novel organic amine molecularcompounds represented by the above formula 1 wherein R is organic amineresidue.

The process of the present invention in which the reaction is carriedout in an organic solvent between the present indolylaliphatic acidderivatives and carbonate or bicarbonate of an alkali metal or organicamines is most advantageous from a commercial point of view to obtainthe desired product in high yield and free from being occluded withcoloring matters, wherein strict control of temperature conditions andproduction operation in a nitrogen stream are not required. Furthermore,novel molecular compounds of arginine, aminopyrine, urotropin, etc. canreadily be obtained by the present process.

The amine salts, aminoacid salts, arginine salts aminopyrine salts,chlorpheniramine salts, urotropine salts and thiamine salts, producedaccording to the process of the present invention are novel compoundwhich the present inventors have first synthesized.

i-acyl-B-indolylaliphatic acid derivatives used in the present inventionare produced according to a process described in the specification ofBelgian Pat. No. 679,678 or 698,378. Examples of thel-acyl-3-indolylaliphatic acid derivatives include the followingcompounds:

1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid a-[l-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolyljpropionic acidl-p-chlorobenzoyl-2-methyl-S-methoxy-3-indolylacetic acidl-nicotinoyl-2-methyl-5-methoxy-3-indolylacetic acidl-isonicotinoyl-2-methyl-5-methoxy-3-indolylacetic acidl-p-chlorobenzoyl-2,5dimethyl-3-indolylacetic acid 1-p-bromobenzoyl-2-methyl-5-methoxy-3-indolylacetic acid in producing analkali metal salt of l-acyl-3-indolylaliphatic acid derivative of theformula (I) wherein R is an alkali metal, a l-acyl-3-indolylaliphaticacid derivative of the formula (I1) is added to an organic solvent suchas methanol or acetone and carbonate or bicarbonate of an alkali metalsuch as sodium or potassium is added to the resultant mixture andfurther a small amount of water is added thereto.

The reaction mixture is stirred to complete the reaction untiloccurrence of carbon dioxide gas ceased.

The solvent is used in an amount sufficient to dissolve or suspend thel-acyl-3-indolylaliphatic acid derivative of the formula (I).

The reaction temperature is from [5 C, to a boiling point of thesolvent, preferably from 50 to 70 C.

The reaction period of time is dependent upon a concentration ofl-acyl-3-indolylaliphatic acid derivative of the formula (ll) in thereaction mixture and the reaction temperature and in many cases thereaction is completed within l hour.

The amount of water added to the reaction mixture is from 5 percent to20 percent, preferably about percent, by volume of the mixturecontaining the organic solvent and the l-acyl-3-indolylaliphatic acidderivative of the formula (II).

After the reaction is over the reaction mixture is subjected toconcentration under reduced pressure to give a residue containing thealkali metal salt of the formula (I) wherein R is an alkali metal.

in production of an organic amine molecular compound of the formula (I)wherein R is an organic amine residue, a lacyl-3-indolylaliphatic acidderivative of the formula (II) is added to an organic solvent such asmethanol or acetone and the organic amine such as ethanolamine,triethanolamine,

diethylaminoethanol, ethylenediamine, histidine, arginine, lysine,omithine, citrullin, glucosamine, aminopyrine, chlorpheniramine,ergotamine, urotropin, thiamine or pyridoxamine is added to theresultant mixture and the reaction mixture is stirred for about 1 hourto complete the reaction.

The amount of the solvent is similar to that of the alkali metal saltformation mentioned above.

it is not always necessary to heat the reaction mixture, but it ispreferably to heat the reaction mixture at 50 to 70 C.

After the reaction is over, the reaction product is separated from thereaction mixture by subjecting the reaction mixture to concentrationunder reduced pressure to obtain the organic amine molecular compound ofthe formula (I) wherein R is an organic amine residue as a crystallineresidue.

in production of an alkaline earth metal salt or aluminum salt of thel-acyl-3-indolylaliphatic acid derivative of the formula (ill) a solublesalt of an alkaline earth metal or aluminum is reacted with the alkalimetal salt of a l-acyl-3-indolylaliphatic acid derivative of the formula(I) in the presence of water to yield the alkaline earth metal salt oraluminum salt.

Examples of the soluble salt of the alkaline earth metal or aluminum aremagnesium chloride, strontium chloride, calcium chloride, aluminumchloride or aluminum sulfate. The reaction between the soluble salt ofthe alkaline earth metal or aluminum and the alkali metal salt of thel-acyl-3-indolylaliphatic acid derivative is completed by only addingthe soluble salt of the alkaline earth metal or aluminum to an aqueoussolution of the alkali metal salt of the l-acyl-S-indolylaliphatic acidderivative and stirring the resultant mixture at room temperature forabout 1 hour.

Only in the case of production of calcium salt of the l-acyl-3-indolylaliphatic acid derivative of the formula (Ill) in which Arepresents pyridyl, the reaction time requires about 24 hours at areaction temperature of room temperature. The desired alkaline earthmetal salt or aluminum salt of the formula (Ill) precipitates in thereaction mixture and is separated from the reaction mixture byfiltration.

Yield of the salt formation or molecular compound formation of thepresent invention is almost quantitative based on the amount of consumedl-acyl-B-indolylaliphatic acid derivative of the formula (ll).

Examples of the salts or molecular compounds thus obtained are asfollows, but the present invention is not limited to them.

Sodium l-isonicotinoyl-2-methyl-5-methoxy- 3 -indolylacetate Potassium1-isonicotinoyl-2-methyl-5-methoxy-3-indolylacetate Sodiuml-nicotinoyl-2-methyl-5-methoxy-3-indolyacetate Potassiuml-nicotinoyl-2-methyl $-methoxy-3-indolylacetate Calciuml-nicotinoyl-2-methyl-S-methoxy-B-indolylacetate Aluminuml-nicotinoyl-2-methyl-5-methoxy-3-indolylacetate Ethanol ammonium saltof l-nicotinoyl-2-methyl-5-methoxy-S-indolylacetic acid Glucosaminiumsalt of l-nicotinoyl-2methyl-5-methoxy-3- indolylacetic acid Sodiuml-nicotinoyl-Z-methyl-S-chloro-3-indolylacetate Sodiuml-nicotinoyl-2,5-dirnethyl-3-indolylacetate Calciuml-nicotinoyl-2,4-dimethyl-3-indolylacetate Sodium1-nicotinoyl-2,6-dimethyl-3-indolylacetate Potassiuma[l-nicotinoyl-2-methyl-5-methoxy-3-indolyl]- propionate Potassium[1-nicotinoyl-2-methyl-5-methoxy-3-indolyl]- butyrate Sodiuml-cinnamoyl-2-methyl-5-rnethoxy-3-indolylacetate Potassiuml-cinr1amoyl-2-rnethyl-5-methoxy 3-indolylacetate Magnesium l-cinnamoyl2-methyl-5-methoxy-3 -indolylacetate Calciuml-cinnamoyl-2-methyl-5-methoxy3-indolylacetate Ethanol ammonium salt ofl-cinnamoyl-Z-methyl-S- methoxy-3-indolylacetic acid N,N-dimethylethanolammonium salt of l-cinnamoyl-Z- methyl-5-methoxy-3-indolylacetic acidGlucosaminium salt of l-cinnamoyl-2-methyl-5-methoxyindolylacetic acidTriethylammonium salt of 1-cinnam0yl-2 methyl-fi-methoxy-3-indolylaceticacid Sodium 1-cinnamoyl2-methyl-5-chloro-3-indolylacetate Potassium1-cinnamoyl-Z-methyl-3-indolylacetate Sodiuml-cinnamoyl-Z-methyl-S-ethoxy-B-indolylacetate Sodium a-(1-cinnamoyl2'methyl5-methoxy-3-indolyl )propionate Sodium [H1-cinnamoyl-2-methyl-5-methoxy-3-indolyl)propionate Sodium a-(l-cinnamoyl-2-methyl-5-methoxy-3-indolyl)butyrate

2. A process according to claim 1, wherein the temperature is 50* - 70*C.
 3. A process according to claim 1, wherein the amount of water isabout 10 percent by volume of said solution.
 4. A process for preparingsodium salt or arginine salt of1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid, whichcomprises dissolving 1 mole of1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid in acetoneand adding to the acetone solution an aqueous solution consisting of 1mole of sodium bicarbonate or 1 mole of arginine and 10 percent byvolume of the acetone solution of water at 50* - 70* C. to yield sodium1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetate or arginine1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetate.